The mission of our Perimenopause in Brain Aging and Alzheimer's Disease Program Project is to discover the biological transformafions that occur in the brain during the perimenopausal transifion that can result in phenotypes predictive of risk for development of AD pathology. The mission of Project 1 is to determine the perimenopausal bioenergetic phenotypes most at risk for developing bioenergetics predictive of AD pathology;delineate the mechanistic pathways involved in development of the at-AD-risk phenotype;and assess the impact of ovarian hormone and nutritional interventions on expression of bioenergetic biomarkers of AD. Ufilizing rodent models of human perimenopause. Project 1 will achieve its mission by determining; (1) in Aim 1 the bioenergefic phenotypes induced by the perimenopausal transition, (2) in Aim 2 the mechanisms that generate the at-AD-risk phenotype and (3) in Aim 3 the window of opportunity to prevent bioenergefic at-AD-risk phenotype. To address our hypotheses, we will experimentally determine bioenergefic gene expression across the perimenopausal transifion and monitor indicators of mitochondrial function which will include: bioinformafics network analyses of gene expression, in vivo cerebral glucose metabolism and synapfic transmission. Mechanisfic analyses will address (1) hypometabolism and cell- specific metabolic profiles, (2) redox control of bioenergefic pathway, and (3) white matter loss. Project 1 collaborates with Projects 2, 3 and 4 to test the hypothesis that decline in brain bioenergetics leads to acfivafion of the infiammatory response in brain (Project 2) which exacerbates mitochondrial funcfion which leads to development of AD pathology (Project 3) and mitochondrial dysfunction is associated with cognifive decline in women assessed through ancillary analyses of the ELITE NIA sponsored clinical trial (Project 4). Outcomes of Project 1 research will include: (1) basic science discovery ofthe bioenergefics ofthe perimenopausal aging transifion in brain regions vulnerable to development of AD pathology;(2) mechanistic pathways that lead to decline in bioenergetics in the perimenopausal brain;(3) translational research discovery of the window of opportunity for ovarian hormone intervenfion to prevent decline in bioenergetics in the perimenopausal brain and (4) clinical associafions of bioenergefic gene expression, mitochondrial funcfion in peripheral blood cells and cognitive decline in postmenopausal women. RELEVANCE (See instructions): More than 60% of Alzheimer's disease (AD) patients are women. Project 1 of our Perimenopause Program Project will determine the impact of the perimenopause transition on the ability of the brain to generate the energy required for cognitive function and to prevent development of Alzheimer's. Project 1 research will also determine the window of opportunity for hormone therapy to prevent decline in brain energy to reduce the risk of Alzheimer's.